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Effects of intravenous and oral disopyramide on paroxysmal atrioventricular nodal tachycardia
Effects of Intravenousand Oral Disopyramide on Paroxysmal AtrioventricularNodal Tachycardia PEDRO BRUGADA, MD, and HEIN J. J. WELLENS, MD
The effect of intravenous and oral disopyramide on the mechanisms of the arrhythmia were studied in 11 patients with the common type of atrioventricular (AV) nodal paroxysmal reentrant tachycardia. Programmed electric stimulation of the heart was used to initiate and terminate tachycardia and to evaluate the effect of disopyramide on mode of initiation and termination of tachycardia. Disopyramide was given intravenously to all patients during tachycardia. This resulted in termination of tachycardia, by block in the anterograde slow pathway in 1 and in the retrograde fast pathway in 3 patients. In all 4 patients, reinitiation of tachycardia was no longer possible. In these 4 patients, oral disopyramide prevented spontaneous and pacing-induced AV nodal tachycardia. In 4 of the remaining 7 patients in whom tachycardia was not terminated by
intravenous disopyramide, reinitiation of the arrhythmia during programmed stimulation was prevented by the drug. In these 4 patients, oral disopyramide was also effective in preventing spontaneous occurrence of tachycardia. In 3 patients, tachycardia was not terminated and its reinitiation was not prevented by intravenous disopyramide. Only 1 of these 3 patients received disopyramide by mouth, and it failed to prevent reinitiation and spontaneous tachycardia. In conclusion, disopyramide is an effective drug in patients with AV nodal paroxysmal reentrant tachycardia. A good correlation was found between intravenous and oral effect of disopyramide on the mechanisms of the arrhythmia. The study of the effect of intravenous disopyramide predicted the outcome of oral disopyramide therapy. (Am J Cardiol 1984;53:88-92)
During programmed stimulation of the heart, propranolol, digitalis, verapamil and procainamide have been shown to be effective in preventing reinitiation of atrioventricular (AV) nodal tachycardia.l-” In some of these studies, a good correlation was found between the inability to initiate tachycardia after administration of an antiarrhythmic during programmed stimulation and clinical efficacy of the same drug.6 However, dissimilar results can be observed with certain antiarrhythmic drugs7; therefore, the effect of the drug must be assessed after intravenous as well as oral administration. In the present study, we investigated the value of intravenous and oral disopyramide for the acute termination and the subsequent prevention of spontaneous and pacinginduced AV nodal tachycardia.
Methods
From the Department of Cardiology, University of Limburg, St. Annadal Hospital, Maastricht, The Netherlands. Manuscript received May 11, 1983; revised manuscript received September 7, 1983, accepted September 10, 1983. Address for reprints: Pedro Brugada, MD, Clinical Electrophysiology Laboratory, Department of Cardiology, University of Limburg, St. Annadal Hospital, Maastricht, The Netherlands.
After giving informed consent, 11 patients who had 3 or more spontaneous episodes per month of paroxysmal AV intranodal tachycardia were studied. Six were men and 5 women, aged 28 to 71 years. Two patients had arteriosclerotic heart disease and 9 had no identifiable structural heart disease. All 11 patients had normal left ventricular function. No patient was receiving medication at the time of study. The reentry circuit was shown to be confined to the AV node using previously reported criteria.x All patients had simultaneous activation of atriums and ventricles using a slow AV nodal pathway for anterograde and a fast AV nodal pathway for retrograde conduction during tachycardia. In no patient was evidence found for the presence of an accessory AV pathway. In the absence of drugs, a sustained AV nodal tachycardia was initiated during programmed stimulation of the heart in all patients. These 11 patients were seen consecutively, but during the period of study 8 patients were not entered. These included 4 patients who had received long-term treatment with oral amiodarone before referral, 2 patients with tachycardia inducible only after atropine, 1 patient with intranodal tachycardia and sustained atria1 fibrillation, and 1 patient in whom only nonsustained tachycardia could be induced after atropine.
January 1, 1984
TABLE Patient
I
89
Electrophysiologic Data and Effect of Intravenous Disopyramide SR-CL
SR-AH
800 700 660 660 820
SR-HV
St?-QRS
BCL
45 70
100 120 80
600 600 500 500
58
600
4”: 45 50 45 45
850 930 800 580
_..
IJ
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
580 750 600 520 420 700 540 710 740 800 570
9: :: 5”: 40 40 48 !8
::
I::* 150’
so0
:8 70 80 80 80 80 80
600 500 500 500 500 450 450
::
400 600 600 600
9”: 80 80 80 90
AHb
500 500
9":
ANTERPf
ANTFRPf
310 310 450 >500 400 >210+ 370 >600 290 <280 290 400 300 <250 240 <220 380 400 270 280 390 320
390 380 500 >600 490 420 600 350 310 390 380 400 380 300 300 470 470 350 420 430 400
ANTERPs 300 <330 (340 (260 (210 270 <250 <270
<300 <260
kid
Gi
300 <270 <280 <250 280
RETERPf
ERPRA
FRPRA
RVERP
<210 470 (260 370 340
230 270 280 290 200 <210 190 200 190 240 190 236 210 190 200 210 220 230 190 220 230 230
260 300 330 340 260 <210 220 280 270 280 220 260 260 250 220 220 280 270 270 280 250 270
210 270 260 270 210
%, 280 210 230 250 260 210 230 190 200 230 240 220 260 210 250
All values are in milliseconds. Patient with catheter-induced riaht bundle branch block. + Longer values not tested. AHb = AH interval during atrial pacing at the cycle length shown; ANTERPf and ANTERPs = anterograde effective refractory period of the fast AV nodal pathway and the slow AV nodal pathway, respectively: ANTFRPf = anterograde functional refractory period of the fast pathway; BCL = basic cycle length of pacing; C = control: D = disopyramide; ERPFtA = effective refractory period of the right atrium; FRPFIA = functional refractory period of the right atrium; RETERPf = retrograde effective refractory period of the fast pathway; RVERP = effective refractory period of the right ventricle; SR-AH = AH interval during sinus rhythm; SR-CL = cycle length during sinus rhythm; SR-HV = HV interval during sinus rhythm: SR-QRS = QRS complex during sinus rhythm: l
During the acute study, 8 of the 11 patients had a coronary sinus (CS) quadripolar catheter inserted for stimulation and recording. Two of the remaining 3 patients who did not have a CS catheter had a quadripolar electrode catheter placed in the pulmonary artery to record left atrial activation indirectly. During extrastimulus testing, at least 2 basic cycle lengths of pacing were used from each stimulation site (right atrium, right ventricle and CS, when available) before and after intravenous disopyramide. During oral disopyramide therapy, only the catheters at the sites where tachycardia was initiated during the acute study were left in place; stimulation at several basic cycle lengths was performed from these sites. During oral disopyramide administration, stimulation was performed from at least 1 atria1 site. By a subsequent change in the position of the catheter, right ventricular stimulation was also performed in all patients. After single and double test stimulation, incremental pacing was done from both the atrium and the ventricle. Stimulation before and after drug administration was performed at twice the diastolic threshold. Continuous recordings were made simultaneously of leads I, II, III, VI and VGand the endocavitary bipolar electrograms of the His bundle area, high right atrium and CS or pulmonary artery. A unipolar or bipolar atria1 or ventricular electrogram or both, but no His bundle recording, was available in all patients during the study performed under oral disopyramide. Modes of disopyramide administration: After initiation of tachycardia and study of its mechanism, disopyramide was given intravenously during tachycardia. A dose of 0.2 mg/kg body weight/min was given until tachycardia was terminated or a total dose of 2.0 mg/kg body weight was administered. Surface and endocavitary electrograms were continuously recorded during drug administration. Blood pressure was measured using the cuff method. When tachycardia was not terminated by intravenous disopyramide, programmed stimulation was restarted 5 minutes after the end of the in-
jection. Tachycardia was then terminated by extrastimuli or overdriving and the previously given stimulation protocol was repeated continuously for 45 minutes. In the Results section, only the maximal changes in electrophysiologic measurements after disopyramide are reported. Nine of the 11 patients subsequently received 600 to 800 mg of oral disopyramide dai!y divided over 3 doses. The stimulation protocol was repeated after 3 days of oral therapy. Plasma levels of disopyramide were not measured.
Results Effect of disopyramide on conduction intervals and refractory periods during sinus rhythm and pacing: Table I shows the effect of disopyramide on the conduction intervals during sinus rhythm (as measured after termination of tachycardia) and the refractory periods of the right atrium, AV nodal pathways and right ventricle. The AH interval during sinus rhythm prolonged in 7 patients. Six patients had a shorter sinus cycle length and 1 a longer sinus cycle length after disopyramide administration. In 3 patients, the AH interval during sinus rhythm did not change. One of these 3 patients had a longer, 1 a shorter and 1 the same sinus cycle length as before the drug. In comparing the same basic cycle length of atrial pacing before and after disopyramide, the AH interval prolonged in 3 patients, shortened in 3 and remained the same in 5 patients. The HV interval during sinus rhythm prolonged by 10 ms in 3 patients, by 5 ms in 1 patient and by 25 ms in 1. The last patient also had a 20-ms widening of the QRS complex after disopyramide. In the other 8 patients, the HV interval during sinus rhythm did not change after intravenous disopyramide.
DISOPYRAMIDE
IN ATRIOVENTRICULAR
NODAL TACHYCARDIA
DIWPYRAMIDE
FIGURE 1. Patient 4-termination of a pacing-induced nonsustained intranodal tachycardia after intravenous disopyramide. Before termination of the arrhythmia by block in the retrograde fast pathway, there was marked prolongation of the HA interval. Five surface leads are shown simultaneously with 2 bipolar electrograms from the high right atrium and His bundle region. Paper speed is 100 mm/s.
Studied at the same basic cycle length of pacing before and after intravenous disopyramide, the anterograde effective refractory period (ANT-ERP) of the fast AV nodal pathway prolonged in 5 patients, shortened in 4 patients and did not change in 1 patient. In 1 patient, the effective refractory period of the fast pathway could not be determined after disopyramide. In 10 patients, the anterograde functional refractory period of the fast AV nodal pathway could be measured before and after the intravenous administration of disopyramide. The functional refractory period of the fast AV nodal pathway shortened in 5 patients, prolonged in 3 and did not change in 2. Measurements of refractoriness in AV nodal conduction over the slow AV nodal pathway was hampered in most patients by the refractory period of the atrium. The ANT-ERP of the slow pathway, however, shortened after intravenous disopyramide administration in 2 patients and was prolonged in 1 patient. Patient 1, who showed continuous anterograde AV nodal conduction curves before disopyramide, had discontinuous anterograde conduction curves after the drug as a result of shortening in the ANT-ERP of the slow pathway. Three patients who had discontinuous curves in anterograde direction before disopyramide had continuous anterograde conduction curves because of marked shortening in the ANT-ERP of the fast AV nodal pathway (Patients 5,7 and 8) being able to conduct up to the refractory period of the atrium. The ERP of the right atrium increased in 8 patients, shortened in 1, did not change in 1 and was not measured in 1 patient. Seven patients had a prolongation of the functional refractory period of the right atrium (FRP-RA) after intravenous disopyramide. The FRP-RA shortened in 2 patients and did not change in 1 patient. In the 1 remaining patient, the FRP-RA
was not measured. The right ventricular refractory period increased in all patients after intravenous disopyramide. Retrograde conduction: The study of the effect of drugs on the different parts of the ventriculoatrial conduction system was hampered by the fact that during basic ventricular pacing, His bundle activation could usually not be determined because the His bundle electrogram was buried within the QRS complex. In 7 patients, however, the retrograde His bundle electrogram was visible after the premature beat during single test stimulation of the ventricle both before and after intravenous disopyramide. Prolongation of the ERP of the retrograde fast AV nodal pathway was observed in 6 patients. In 1 patient, the ERP of the fast pathway shortened in the retrograde direction. Effect of intravenous disopyramide when given during tachycardia (Table II): Disopyramide prolonged the cycle length of the tachycardia in 7 patients, and did not change it in 4 patients. The increase in tachycardia cycle length was due to an increase in HA interval in 1 patient, an increase in AH interval in 2 patients and an increase in both AH and HA interval in 4 patients. In 4 patients (Patients 1 to 4) tachycardia was terminated. Block occurred in the slow anterograde pathway in Patient 1 and in the retrograde fast pathway in Patients 2,3 and 4. In Patients 3 and 4, marked prolongation of the retrograde fast pathway conduction time occurred before termination of the arrhythmia (Fig. 1). In 7 patients, tachycardia had to be terminated by pacing. Disopyramide did not facilitate termination of tachycardia even after slowing in tachycardia rate. Patient 5, in whom tachycardia could be terminated by a single high right atria1 premature beat before disopyramide, also required a single atria1 premature beat after the drug. Patient 10, however, required atria1
January 1, 1984
TABLE II
JOURNAL OF CARDIOLOGY
\/olume 53
91
Effect of Intravenous and Oral Disopyramide on Atrioventricular Nodal Tachycardia
Patient 1
THE AMERICAN
C
Termination of TAC
Total D Dose
1 APB Drug-induced slow
1 VPB NI NI
1.0 600
1 APB Drug-induced fast
1 APB 1 APB” NI
1.1 600
210 270
2 APBs Drug-induced fast
2 APBs 2 APBs” NI
1.5 600
390 380
300 260
2 APBs Drug-induced fast
1 APB 1 APB” NI
1.0 800
380 470
330 420
1 APB 1 APB
1 APB NI NI
2.0 600
270 330
220 250
2 APBs 2 APBs
1 APB NI NI
2.0 600
370 370
290 260
80 110 .
2 APBs 2 APBs
1 APB NI NI
1.5 800
290 320
220 250
70 70
Overdrive Overdrive
1 APB NI NI
2.0 600
340 375
290 315 Not given
;o”
2 APBs 2 APBs
1 APB 1 APB
2.0
310 310
270 270 Not given
40 40
1 APB Spont fast/overdrive
1 APB 1 APB
1.0
300 390 380
260 340,
40 50
2 APBs Overdrive pacing Spontloverdrive
1 APB 1 APB 1 APB
2.0 600
440 445
400 380
:5”
375 375
335 325 .
5”:
C ivD oD
270 360
C ivD oD
C
ivD oD
Mode of Initiation
L
C ivD oD 3
4
5
ivD oD 6
C ivD oD
.
7 C ivD
oD 8 ivD oD 9 C ivD oD 10 C ivD oD 11 C ivD oD
.
t
* Nonsustained tachycardia initiated. t His bundle recording not available. AH = AH interval during tachycardia; APB = atrial premature beat; C = control; CL = cycle length of the tachycardia; D = disopyramide; HA = HA interval during tachycardia; ivD = intravenous disopyramide (mg/kg body weight); NI = not inducible: oD = oral disopyramide (mg/day); Spont = spontaneous termination; termination of TAC = mode of termination of tachycardia.
overdrive pacing to terminate tachycardia instead of a single atria1 premature beat as before disopyramide. Later, this patient had spontaneous termination of the arrhythmia by block in the retrograde fast pathway. Of the 4 patients who required double atria1 premature beats to terminate tachycardia before disopyramide, 3 required the same number of premature beats after administration of the drug. The remaining patient required overdrive pacing to terminate the arrhythmia. Reinitiation
of tachycardia
after
disopyramide:
After termination of tachycardia, reinitiation of a sustained tachycardia was not possible in 8 patients, including those in whom tachycardia was terminated by the intravenous administration of disopyramide. In Patients 2, 3 and 4, a nonsustained tachycardia could still be initiated (Fig. 1) within 10 minutes after administration of disopyramide. Twelve to 30 minutes after injection, no tachycardia could be initiated in these patients. In 3 patients, sustained tachycardia was again initiated by a single atria1 premature beat.
Oral disopyramide (Table II): Oral disopyramide prevented spontaneous episodes of tachycardia during 72-hour monitoring in 8 of the 9 patients. In Patient 11, spontaneous episodes of tachycardia initiated by atria1 premature beats were observed. In this patient, the arrhythmia could also be initiated by a single atria1 test stimulus. In the remaining 8 patients, tachycardia could not be initiated by programmed stimulation during oral disopyramide. In these patients, no spontaneous episodes of tachycardia developed during a follow-up of 6 to 12 months with disopyramide. Side effects of intravenous and oral disopyramide: The total intravenous and daily oral doses of diso-
pyramide received by each patient are shown in Table II. Infusion of disopyramide was stopped in Patients 1 to 4 when tachycardia was terminated. In Patient 10, the infusion was stopped after 1.0 mglkg body weight because of complaints of headache. Three patients showed slight reductions in systolic blood pressure (20 to 30 mm Hg).
92
DISOPYRAMIDE
IN ATRIOVENTRICULAR
NODAL TACHYCARDIA
Patient 7 complained of nausea and 3 other patients of a dry mouth during oral disopyramide therapy. It was not necessary, however, to stop the drug in any of them. Discussion This study shows the high efficacy of disopyramide in paroxysmal AV intranodal tachycardia. Intravenous disopyramide terminated tachycardia acutely in 4 of 11 patients. Pacing-induced tachycardia was prevented in 8 patients. In all 8 patients in whom intravenous disopyramide terminated or prevented pacing-induced tachycardia, spontaneous and pacing-induced episodes of the arrhythmia were prevented by administration of oral disopyramide. The mechanism of prevention of initiation of tachycardia varied from patient to patient. This differs from the rather uniform results reported with other drugs, with the exception of procainamide.1-5 Swiryn et al9 also observed marked effects of disopyramide on both the anterograde and retrograde limbs in patients with intranodal reentry, although the effects on the retrograde limb predominated. In our Patient 1,tachycardia was initiated by a ventricular premature beat, but not by atria1 premature beats during the control study. Tachycardia terminated by block in the anterograde slow pathway. Reinitiation after intravenous and oral disopyramide was, however, prevented by marked prolongation of the retrograde fast pathway refractory period. In Patient 2, exclusive prolongation of the refractory period of the retrograde fast pathway seemed to be the mechanism of prevention of tachycardia. In Patients 3 and 4, a decrease in the maximal AH interval over the slow anterograde pathway probably prevented arrival of the impulse at the retrograde fast pathway at a time outside its refractory period. Shortening of the anterograde effective refractory period of the fast pathway by disopyramide changed the anterograde AV nodal conduction curve from a discontinuous into a continuous one in Patients 5, 7 and 8, with resulting inability to initiate tachycardia. Patients 5 and 7 also showed prolongation of the retrograde refractory period of the fast pathway, in contrast to the shortening of the refractory period of this pathway in the anterograde direction. Prolongation of the refractory period of the retrograde pathway and shortening of the maximal AH interval over the anterograde slow pathway prevented reinitiation of tachycardia in Patient 6. A delicate interplay between refractory periods and conduction velocities of the components of the circuit is required to initiate and maintain reentry. This balance can be disrupted by drugs and changes in autonomic tone. Disopyramide, in addition to its class I antiarrhythmic properties, has marked vagolytic effects.1*-L2 Pre-
vention of tachycardia can be explained by a combination of these 2 effects in Patients 5,6 and 7. In Patients 3, 4 and 8, the vagolytic effects of the drug probably accounted for changes in the electrophysiologic properties of the AV nodal pathways and for the inability to initiate and sustain a tachycardia. In Patients 1 and 2, the most important mechanism preventing initiation of tachycardia was prolongation of the retrograde fast pathway refractory period. This mode of prevention of tachycardia is similar to that reported after administration of procainamide.5 As opposed to some patients studied by Wu et al,5 all of our patients had a sustained tachycardia initiated before drug administration. Therefore, we did not observe sustainment of a previously self-terminating arrhythmia after disopyramide. Theoretically, as with procainamide,” this can be expected because of the vagolytic effect of the drug. In conclusion, disopyramide is an effective drug for terminating and preventing spontaneous and pacinginduced episodes of paroxysmal AV intranodal tachycardia. The effect during intravenous administration correlated with the effect after oral administration of the drug and predicted the clinical course with oral disopyramide. Both vagolytic and class I effects of disopyramide appear to play a role in preventing initiation and perpetuation of AV intranodal tachycardia.
References
5. 6.
7. 6. 9.
10. 11.
12.
Wu 0, Oenes P, Ohingra R, Khan A, Rosen K. The effects of propranolol on induction of A-V nodal re-entrant paroxysmal tachycardia. Circulation 1974;50:665-667. Wu 0, Wyndham C, Amat-y-Leon F, Oenes 9, Ohingra RC, Rosen KM. The effects of ouabain on induction of atrioventncular nodal re-entrant paroxysmal supraventricular tachycardia. Circulation 1975;52:201-207. Wellens HJJ, Oiiren 09, Liem KL, Lie KI. Effect of digitalis in patients with paroxysmal atrioventrlcular nodal tachycardia. Circulation 1975;52: 779-700. Wellens HJJ, Tan SL, Bdr FWH, Ouren OR, Lle KI, Oohmen HN. Effect of verapamil studied by programmed electrical stimulation of the heart in patients with paroxysmal re-entrant supraventricular tachycardia. Br Heart J. 1977;39:1058-1066. Wu 0, Oenes P, Bauernfelncl R, Kehoe R, Amat-y-Leon F, Rosen KM. Effect of procainamids on atrioventricular nodal reentrant paroxysmal tachycardia. Circulation 1978;57:1171-1179. Wu 0, Wyndham CR, Oenes P, Amaf-y-Leon F, Miller RH, Ohingra RC, Rosen KM. Chronic electrophysiological study in patients with recurrent paroxysmal tachycardia: a new method for developing successful oral antiarrhythmic therapy. In: Kulbertus HE, ed. Re-entrant Arrhythmias. Lancaster: MTP Press, 1977:294-311, Wellens HJJ, Brugada P, Roy 0, Heddle F, Bar F. A comparison of the electrophysiologic effects of intravenous and oral amiodarone (abstr). Am J Cardiol 1982;49:1043. Brugada P, ROSSOL, Biir FWH, Vanagt EJ, Oassen WRM, Wellens HJJ. Observations on spontaneous termination of atrioventricular nodal reentrant tachycardia. Am J Cardiol 1981;47:703-707. Swfryn S, Bauernfelnd RA, Wyndham CRC, Ohfngra RC, Paliko E, Strasberg B, Rosen KM. Effects of oral disopyramide phosphate on induction of paroxysmal supraventricular tachycardia. Circulation 1981;64:169175. Josephson ME Caracta AR, Lau SH, Gallagher JJ, Oamato AN. Electrophysiological evaluation of disopyramide in man. Am Heart J 1978;86: 771-780. Spurrell RA?, Thornburn CW, Camm J, Sowton E, Oeuchar DC. Effects of disopyramlde on electrophysiological properties of specialized conduction system in man and on accessory atrio-ventricular pathway in Wolff-Parkinson-white syndrome. Br Heart J 1975;37:861-867. Ross 0, Vohra J, Cole P, Hunt 0, Sloman 0. Electrophysiology of disopyramide in man. Aust NZ J Med 1978;8:377-303.
The effect of intravenous and oral disopyramide on the mechanisms of the arrhythmia were studied in 11 patients with the common type of atrioventricular (AV) nodal paroxysmal reentrant tachycardia. Programmed electric stimulation of the heart was used to initiate and terminate tachycardia and to evaluate the effect of disopyramide on mode of initiation and termination of tachycardia. Disopyramide was given intravenously to all patients during tachycardia. This resulted in termination of tachycardia, by block in the anterograde slow pathway in 1 and in the retrograde fast pathway in 3 patients. In all 4 patients, reinitiation of tachycardia was no longer possible. In these 4 patients, oral disopyramide prevented spontaneous and pacing-induced AV nodal tachycardia. In 4 of the remaining 7 patients in whom tachycardia was not terminated by
intravenous disopyramide, reinitiation of the arrhythmia during programmed stimulation was prevented by the drug. In these 4 patients, oral disopyramide was also effective in preventing spontaneous occurrence of tachycardia. In 3 patients, tachycardia was not terminated and its reinitiation was not prevented by intravenous disopyramide. Only 1 of these 3 patients received disopyramide by mouth, and it failed to prevent reinitiation and spontaneous tachycardia. In conclusion, disopyramide is an effective drug in patients with AV nodal paroxysmal reentrant tachycardia. A good correlation was found between intravenous and oral effect of disopyramide on the mechanisms of the arrhythmia. The study of the effect of intravenous disopyramide predicted the outcome of oral disopyramide therapy. (Am J Cardiol 1984;53:88-92)
During programmed stimulation of the heart, propranolol, digitalis, verapamil and procainamide have been shown to be effective in preventing reinitiation of atrioventricular (AV) nodal tachycardia.l-” In some of these studies, a good correlation was found between the inability to initiate tachycardia after administration of an antiarrhythmic during programmed stimulation and clinical efficacy of the same drug.6 However, dissimilar results can be observed with certain antiarrhythmic drugs7; therefore, the effect of the drug must be assessed after intravenous as well as oral administration. In the present study, we investigated the value of intravenous and oral disopyramide for the acute termination and the subsequent prevention of spontaneous and pacinginduced AV nodal tachycardia.
Methods
From the Department of Cardiology, University of Limburg, St. Annadal Hospital, Maastricht, The Netherlands. Manuscript received May 11, 1983; revised manuscript received September 7, 1983, accepted September 10, 1983. Address for reprints: Pedro Brugada, MD, Clinical Electrophysiology Laboratory, Department of Cardiology, University of Limburg, St. Annadal Hospital, Maastricht, The Netherlands.
After giving informed consent, 11 patients who had 3 or more spontaneous episodes per month of paroxysmal AV intranodal tachycardia were studied. Six were men and 5 women, aged 28 to 71 years. Two patients had arteriosclerotic heart disease and 9 had no identifiable structural heart disease. All 11 patients had normal left ventricular function. No patient was receiving medication at the time of study. The reentry circuit was shown to be confined to the AV node using previously reported criteria.x All patients had simultaneous activation of atriums and ventricles using a slow AV nodal pathway for anterograde and a fast AV nodal pathway for retrograde conduction during tachycardia. In no patient was evidence found for the presence of an accessory AV pathway. In the absence of drugs, a sustained AV nodal tachycardia was initiated during programmed stimulation of the heart in all patients. These 11 patients were seen consecutively, but during the period of study 8 patients were not entered. These included 4 patients who had received long-term treatment with oral amiodarone before referral, 2 patients with tachycardia inducible only after atropine, 1 patient with intranodal tachycardia and sustained atria1 fibrillation, and 1 patient in whom only nonsustained tachycardia could be induced after atropine.
January 1, 1984
TABLE Patient
I
89
Electrophysiologic Data and Effect of Intravenous Disopyramide SR-CL
SR-AH
800 700 660 660 820
SR-HV
St?-QRS
BCL
45 70
100 120 80
600 600 500 500
58
600
4”: 45 50 45 45
850 930 800 580
_..
IJ
THE AMERICAN JOURNAL OF CARDIOLOGY Volume 53
580 750 600 520 420 700 540 710 740 800 570
9: :: 5”: 40 40 48 !8
::
I::* 150’
so0
:8 70 80 80 80 80 80
600 500 500 500 500 450 450
::
400 600 600 600
9”: 80 80 80 90
AHb
500 500
9":
ANTERPf
ANTFRPf
310 310 450 >500 400 >210+ 370 >600 290 <280 290 400 300 <250 240 <220 380 400 270 280 390 320
390 380 500 >600 490 420 600 350 310 390 380 400 380 300 300 470 470 350 420 430 400
ANTERPs 300 <330 (340 (260 (210 270 <250 <270
<300 <260
kid
Gi
300 <270 <280 <250 280
RETERPf
ERPRA
FRPRA
RVERP
<210 470 (260 370 340
230 270 280 290 200 <210 190 200 190 240 190 236 210 190 200 210 220 230 190 220 230 230
260 300 330 340 260 <210 220 280 270 280 220 260 260 250 220 220 280 270 270 280 250 270
210 270 260 270 210
%, 280 210 230 250 260 210 230 190 200 230 240 220 260 210 250
All values are in milliseconds. Patient with catheter-induced riaht bundle branch block. + Longer values not tested. AHb = AH interval during atrial pacing at the cycle length shown; ANTERPf and ANTERPs = anterograde effective refractory period of the fast AV nodal pathway and the slow AV nodal pathway, respectively: ANTFRPf = anterograde functional refractory period of the fast pathway; BCL = basic cycle length of pacing; C = control: D = disopyramide; ERPFtA = effective refractory period of the right atrium; FRPFIA = functional refractory period of the right atrium; RETERPf = retrograde effective refractory period of the fast pathway; RVERP = effective refractory period of the right ventricle; SR-AH = AH interval during sinus rhythm; SR-CL = cycle length during sinus rhythm; SR-HV = HV interval during sinus rhythm: SR-QRS = QRS complex during sinus rhythm: l
During the acute study, 8 of the 11 patients had a coronary sinus (CS) quadripolar catheter inserted for stimulation and recording. Two of the remaining 3 patients who did not have a CS catheter had a quadripolar electrode catheter placed in the pulmonary artery to record left atrial activation indirectly. During extrastimulus testing, at least 2 basic cycle lengths of pacing were used from each stimulation site (right atrium, right ventricle and CS, when available) before and after intravenous disopyramide. During oral disopyramide therapy, only the catheters at the sites where tachycardia was initiated during the acute study were left in place; stimulation at several basic cycle lengths was performed from these sites. During oral disopyramide administration, stimulation was performed from at least 1 atria1 site. By a subsequent change in the position of the catheter, right ventricular stimulation was also performed in all patients. After single and double test stimulation, incremental pacing was done from both the atrium and the ventricle. Stimulation before and after drug administration was performed at twice the diastolic threshold. Continuous recordings were made simultaneously of leads I, II, III, VI and VGand the endocavitary bipolar electrograms of the His bundle area, high right atrium and CS or pulmonary artery. A unipolar or bipolar atria1 or ventricular electrogram or both, but no His bundle recording, was available in all patients during the study performed under oral disopyramide. Modes of disopyramide administration: After initiation of tachycardia and study of its mechanism, disopyramide was given intravenously during tachycardia. A dose of 0.2 mg/kg body weight/min was given until tachycardia was terminated or a total dose of 2.0 mg/kg body weight was administered. Surface and endocavitary electrograms were continuously recorded during drug administration. Blood pressure was measured using the cuff method. When tachycardia was not terminated by intravenous disopyramide, programmed stimulation was restarted 5 minutes after the end of the in-
jection. Tachycardia was then terminated by extrastimuli or overdriving and the previously given stimulation protocol was repeated continuously for 45 minutes. In the Results section, only the maximal changes in electrophysiologic measurements after disopyramide are reported. Nine of the 11 patients subsequently received 600 to 800 mg of oral disopyramide dai!y divided over 3 doses. The stimulation protocol was repeated after 3 days of oral therapy. Plasma levels of disopyramide were not measured.
Results Effect of disopyramide on conduction intervals and refractory periods during sinus rhythm and pacing: Table I shows the effect of disopyramide on the conduction intervals during sinus rhythm (as measured after termination of tachycardia) and the refractory periods of the right atrium, AV nodal pathways and right ventricle. The AH interval during sinus rhythm prolonged in 7 patients. Six patients had a shorter sinus cycle length and 1 a longer sinus cycle length after disopyramide administration. In 3 patients, the AH interval during sinus rhythm did not change. One of these 3 patients had a longer, 1 a shorter and 1 the same sinus cycle length as before the drug. In comparing the same basic cycle length of atrial pacing before and after disopyramide, the AH interval prolonged in 3 patients, shortened in 3 and remained the same in 5 patients. The HV interval during sinus rhythm prolonged by 10 ms in 3 patients, by 5 ms in 1 patient and by 25 ms in 1. The last patient also had a 20-ms widening of the QRS complex after disopyramide. In the other 8 patients, the HV interval during sinus rhythm did not change after intravenous disopyramide.
DISOPYRAMIDE
IN ATRIOVENTRICULAR
NODAL TACHYCARDIA
DIWPYRAMIDE
FIGURE 1. Patient 4-termination of a pacing-induced nonsustained intranodal tachycardia after intravenous disopyramide. Before termination of the arrhythmia by block in the retrograde fast pathway, there was marked prolongation of the HA interval. Five surface leads are shown simultaneously with 2 bipolar electrograms from the high right atrium and His bundle region. Paper speed is 100 mm/s.
Studied at the same basic cycle length of pacing before and after intravenous disopyramide, the anterograde effective refractory period (ANT-ERP) of the fast AV nodal pathway prolonged in 5 patients, shortened in 4 patients and did not change in 1 patient. In 1 patient, the effective refractory period of the fast pathway could not be determined after disopyramide. In 10 patients, the anterograde functional refractory period of the fast AV nodal pathway could be measured before and after the intravenous administration of disopyramide. The functional refractory period of the fast AV nodal pathway shortened in 5 patients, prolonged in 3 and did not change in 2. Measurements of refractoriness in AV nodal conduction over the slow AV nodal pathway was hampered in most patients by the refractory period of the atrium. The ANT-ERP of the slow pathway, however, shortened after intravenous disopyramide administration in 2 patients and was prolonged in 1 patient. Patient 1, who showed continuous anterograde AV nodal conduction curves before disopyramide, had discontinuous anterograde conduction curves after the drug as a result of shortening in the ANT-ERP of the slow pathway. Three patients who had discontinuous curves in anterograde direction before disopyramide had continuous anterograde conduction curves because of marked shortening in the ANT-ERP of the fast AV nodal pathway (Patients 5,7 and 8) being able to conduct up to the refractory period of the atrium. The ERP of the right atrium increased in 8 patients, shortened in 1, did not change in 1 and was not measured in 1 patient. Seven patients had a prolongation of the functional refractory period of the right atrium (FRP-RA) after intravenous disopyramide. The FRP-RA shortened in 2 patients and did not change in 1 patient. In the 1 remaining patient, the FRP-RA
was not measured. The right ventricular refractory period increased in all patients after intravenous disopyramide. Retrograde conduction: The study of the effect of drugs on the different parts of the ventriculoatrial conduction system was hampered by the fact that during basic ventricular pacing, His bundle activation could usually not be determined because the His bundle electrogram was buried within the QRS complex. In 7 patients, however, the retrograde His bundle electrogram was visible after the premature beat during single test stimulation of the ventricle both before and after intravenous disopyramide. Prolongation of the ERP of the retrograde fast AV nodal pathway was observed in 6 patients. In 1 patient, the ERP of the fast pathway shortened in the retrograde direction. Effect of intravenous disopyramide when given during tachycardia (Table II): Disopyramide prolonged the cycle length of the tachycardia in 7 patients, and did not change it in 4 patients. The increase in tachycardia cycle length was due to an increase in HA interval in 1 patient, an increase in AH interval in 2 patients and an increase in both AH and HA interval in 4 patients. In 4 patients (Patients 1 to 4) tachycardia was terminated. Block occurred in the slow anterograde pathway in Patient 1 and in the retrograde fast pathway in Patients 2,3 and 4. In Patients 3 and 4, marked prolongation of the retrograde fast pathway conduction time occurred before termination of the arrhythmia (Fig. 1). In 7 patients, tachycardia had to be terminated by pacing. Disopyramide did not facilitate termination of tachycardia even after slowing in tachycardia rate. Patient 5, in whom tachycardia could be terminated by a single high right atria1 premature beat before disopyramide, also required a single atria1 premature beat after the drug. Patient 10, however, required atria1
January 1, 1984
TABLE II
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91
Effect of Intravenous and Oral Disopyramide on Atrioventricular Nodal Tachycardia
Patient 1
THE AMERICAN
C
Termination of TAC
Total D Dose
1 APB Drug-induced slow
1 VPB NI NI
1.0 600
1 APB Drug-induced fast
1 APB 1 APB” NI
1.1 600
210 270
2 APBs Drug-induced fast
2 APBs 2 APBs” NI
1.5 600
390 380
300 260
2 APBs Drug-induced fast
1 APB 1 APB” NI
1.0 800
380 470
330 420
1 APB 1 APB
1 APB NI NI
2.0 600
270 330
220 250
2 APBs 2 APBs
1 APB NI NI
2.0 600
370 370
290 260
80 110 .
2 APBs 2 APBs
1 APB NI NI
1.5 800
290 320
220 250
70 70
Overdrive Overdrive
1 APB NI NI
2.0 600
340 375
290 315 Not given
;o”
2 APBs 2 APBs
1 APB 1 APB
2.0
310 310
270 270 Not given
40 40
1 APB Spont fast/overdrive
1 APB 1 APB
1.0
300 390 380
260 340,
40 50
2 APBs Overdrive pacing Spontloverdrive
1 APB 1 APB 1 APB
2.0 600
440 445
400 380
:5”
375 375
335 325 .
5”:
C ivD oD
270 360
C ivD oD
C
ivD oD
Mode of Initiation
L
C ivD oD 3
4
5
ivD oD 6
C ivD oD
.
7 C ivD
oD 8 ivD oD 9 C ivD oD 10 C ivD oD 11 C ivD oD
.
t
* Nonsustained tachycardia initiated. t His bundle recording not available. AH = AH interval during tachycardia; APB = atrial premature beat; C = control; CL = cycle length of the tachycardia; D = disopyramide; HA = HA interval during tachycardia; ivD = intravenous disopyramide (mg/kg body weight); NI = not inducible: oD = oral disopyramide (mg/day); Spont = spontaneous termination; termination of TAC = mode of termination of tachycardia.
overdrive pacing to terminate tachycardia instead of a single atria1 premature beat as before disopyramide. Later, this patient had spontaneous termination of the arrhythmia by block in the retrograde fast pathway. Of the 4 patients who required double atria1 premature beats to terminate tachycardia before disopyramide, 3 required the same number of premature beats after administration of the drug. The remaining patient required overdrive pacing to terminate the arrhythmia. Reinitiation
of tachycardia
after
disopyramide:
After termination of tachycardia, reinitiation of a sustained tachycardia was not possible in 8 patients, including those in whom tachycardia was terminated by the intravenous administration of disopyramide. In Patients 2, 3 and 4, a nonsustained tachycardia could still be initiated (Fig. 1) within 10 minutes after administration of disopyramide. Twelve to 30 minutes after injection, no tachycardia could be initiated in these patients. In 3 patients, sustained tachycardia was again initiated by a single atria1 premature beat.
Oral disopyramide (Table II): Oral disopyramide prevented spontaneous episodes of tachycardia during 72-hour monitoring in 8 of the 9 patients. In Patient 11, spontaneous episodes of tachycardia initiated by atria1 premature beats were observed. In this patient, the arrhythmia could also be initiated by a single atria1 test stimulus. In the remaining 8 patients, tachycardia could not be initiated by programmed stimulation during oral disopyramide. In these patients, no spontaneous episodes of tachycardia developed during a follow-up of 6 to 12 months with disopyramide. Side effects of intravenous and oral disopyramide: The total intravenous and daily oral doses of diso-
pyramide received by each patient are shown in Table II. Infusion of disopyramide was stopped in Patients 1 to 4 when tachycardia was terminated. In Patient 10, the infusion was stopped after 1.0 mglkg body weight because of complaints of headache. Three patients showed slight reductions in systolic blood pressure (20 to 30 mm Hg).
92
DISOPYRAMIDE
IN ATRIOVENTRICULAR
NODAL TACHYCARDIA
Patient 7 complained of nausea and 3 other patients of a dry mouth during oral disopyramide therapy. It was not necessary, however, to stop the drug in any of them. Discussion This study shows the high efficacy of disopyramide in paroxysmal AV intranodal tachycardia. Intravenous disopyramide terminated tachycardia acutely in 4 of 11 patients. Pacing-induced tachycardia was prevented in 8 patients. In all 8 patients in whom intravenous disopyramide terminated or prevented pacing-induced tachycardia, spontaneous and pacing-induced episodes of the arrhythmia were prevented by administration of oral disopyramide. The mechanism of prevention of initiation of tachycardia varied from patient to patient. This differs from the rather uniform results reported with other drugs, with the exception of procainamide.1-5 Swiryn et al9 also observed marked effects of disopyramide on both the anterograde and retrograde limbs in patients with intranodal reentry, although the effects on the retrograde limb predominated. In our Patient 1,tachycardia was initiated by a ventricular premature beat, but not by atria1 premature beats during the control study. Tachycardia terminated by block in the anterograde slow pathway. Reinitiation after intravenous and oral disopyramide was, however, prevented by marked prolongation of the retrograde fast pathway refractory period. In Patient 2, exclusive prolongation of the refractory period of the retrograde fast pathway seemed to be the mechanism of prevention of tachycardia. In Patients 3 and 4, a decrease in the maximal AH interval over the slow anterograde pathway probably prevented arrival of the impulse at the retrograde fast pathway at a time outside its refractory period. Shortening of the anterograde effective refractory period of the fast pathway by disopyramide changed the anterograde AV nodal conduction curve from a discontinuous into a continuous one in Patients 5, 7 and 8, with resulting inability to initiate tachycardia. Patients 5 and 7 also showed prolongation of the retrograde refractory period of the fast pathway, in contrast to the shortening of the refractory period of this pathway in the anterograde direction. Prolongation of the refractory period of the retrograde pathway and shortening of the maximal AH interval over the anterograde slow pathway prevented reinitiation of tachycardia in Patient 6. A delicate interplay between refractory periods and conduction velocities of the components of the circuit is required to initiate and maintain reentry. This balance can be disrupted by drugs and changes in autonomic tone. Disopyramide, in addition to its class I antiarrhythmic properties, has marked vagolytic effects.1*-L2 Pre-
vention of tachycardia can be explained by a combination of these 2 effects in Patients 5,6 and 7. In Patients 3, 4 and 8, the vagolytic effects of the drug probably accounted for changes in the electrophysiologic properties of the AV nodal pathways and for the inability to initiate and sustain a tachycardia. In Patients 1 and 2, the most important mechanism preventing initiation of tachycardia was prolongation of the retrograde fast pathway refractory period. This mode of prevention of tachycardia is similar to that reported after administration of procainamide.5 As opposed to some patients studied by Wu et al,5 all of our patients had a sustained tachycardia initiated before drug administration. Therefore, we did not observe sustainment of a previously self-terminating arrhythmia after disopyramide. Theoretically, as with procainamide,” this can be expected because of the vagolytic effect of the drug. In conclusion, disopyramide is an effective drug for terminating and preventing spontaneous and pacinginduced episodes of paroxysmal AV intranodal tachycardia. The effect during intravenous administration correlated with the effect after oral administration of the drug and predicted the clinical course with oral disopyramide. Both vagolytic and class I effects of disopyramide appear to play a role in preventing initiation and perpetuation of AV intranodal tachycardia.
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